Aortic stenosis (AS) is the most common form of valve disease in the western world and affects over 2.5 million individuals in the US. Despite the large burden of disease, there are no medical treatments to slow its development, due in large part to our incomplete understanding of this disease. With the expected increase in the burden of AS due to the aging US population, research targeted to understanding the risk factors and causes of AS is needed, and could lead to new treatment strategies. We recently reported in the New England Journal of Medicine, that genetic variants in LPA are strongly associated with aortic valve calcium (AVC) and clinical AS implicating circulating lipoprotein(a), an usual form of cholesterol as a cause of aortic stenosis. Although the role of Lp(a) is not fully understood, Lp(a) is a major carrier of circulating oxidized phospholipids (oxPL) and lipoprotein-associated phospholipase A2 (LpPLA2). OxPLs (and by-products of their cleavage by LpPLA2) are pro-atherogenic, pro-inflammatory and pro-calcifying, suggesting that oxPL and Lp-PLA2 may be major determinants of Lp(a)-mediated AS. We propose to characterize the relations of Lp(a), oxPL and LpPLA2 and their potential interactions with AVC prevalence cross-sectionally and progression longitudinally, using molecular and genetic epidemiology methods in the Framingham Offspring Study (FOS) and the Multi- Ethnic Study of Atherosclerosis (MESA). By combining two large ongoing NHLBI cohorts, we will create one of the largest cohorts worldwide with sequential valve imaging (n= 7,178; including sequential AVC measurements in 6,777 participants) to address the following aims: Specific Aim 1. To relate circulating levels of Lp(a), oxPL and LpPLA2 to the presence and progression of AVC in FOS and MESA participants and determine their relative contributions to AVC using formal mediation and/or discordance analysis. We will include 1,298 FOS participants and 5,880 MESA participants with available AVC data and relate the biomarker levels to AVC prevalence cross-sectionally and to AVC progression longitudinally using multivariable analyses adjusting for known confounders. Specific Aim 2. To evaluate for effect modification of Lp(a) (and/or oxPL) by LDL-C and/or predisposition to inflammation in the relations with presence and progression of AVC in FHS and MESA participants. We will develop multivariable models incorporating appropriate interaction terms to evaluate AVC prevalence cross- sectionally and AVC progression longitudinally. Specific Aim 3. To provide evidence in support of a causal association between these biomarkers and AVC presence/progression using Mendelian randomization in FHS and MESA participants. Our proposed project is well-aligned with the recommendations of the 2011 National Heart Lung and Blood Institute's AS Working Group and proposes to directly address several important research priorities. Findings from our proposed project will lead to new insights into the pathogenesis of AVC and may inform novel approaches for the prevention and treatment of AS.